Resolving a Natural Product Cold Case: Elucidation of Fusapyrone Structure and Absolute Configuration and Demonstration of Their Fungal Biofilm Disrupting Properties

Fusapyrones are fungal metabolites, which have been reportedtohave broad-spectrum antibacterial and antifungal properties. Despitethe first members of this chemical class being described three decadesprior, many aspects of their structures have remained unresolved,thereby constraining efforts to fully understand structure-activityrelationships within this metabolite family and impeding the designof streamlined syntheses. Among the main challenges posed by fusapyronesis the incorporation of several single and groups of stereocentersseparated by atoms with freely rotating bonds, which have proven unyieldingto spectroscopic analyses. In this study, we obtained a series ofnew (2-5 and 7-9) and previously reported fusapyrones (1 and 6), which were subjected to a combination of spectroscopic,chemical, and computational techniques enabling us to offer proposalsfor their full structures, as well as provide a pathway to reinterpretingthe absolute configurations of other published fusapyrone metabolites.Biological testing of the fusapyrones revealed their abilities toinhibit and disrupt biofilms made by the human fungal pathogen, Candida albicans. These results show that fusapyronesreduce hyphae formation in C. albicans, as well as decrease the surface adherence capabilities of planktoniccells and cells transitioning into early-stage biofilm formation.

Automated summary

Fusapyrones are fungal metabolites with broad-spectrum antibacterial and antifungal properties. This study successfully determined the full structures of fusapyrones and reinterpreted the absolute configurations of previously published metabolites using spectroscopic, chemical, and computational techniques. Biological testing demonstrated that fusapyrones inhibit and disrupt biofilm formation by Candida albicans, a human fungal pathoge.